Xun Zhou1, Hongyan Huang2, Runcheng He3, Sheng Zeng4, Zhenhua Liu3,5,6, Qian Xu3,5,6, Jifeng Guo3,5,6, Xinxiang Yan3,5,6, Ranhui Duan7, Jinchen Li1,3,5,7, Beisha Tang1,3,5,6,7, Yanming Xu2, Qiying Sun1,5,6. 1. Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China. 2. Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. 3. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China. 4. Department of Geriatric Neurology, Second Xiangya Hospital, Central South University, Changsha, China. 5. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. 6. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China. 7. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Abstract
BACKGROUND AND PURPOSE: NOTCH2NLC GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with NOTCH2NLC repeat expansions versus non-expansions and describe distinctive clinical features of repeat expanded patients with long-term follow-up according to the new tremor classification. METHODS: Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in NOTCH2NLC were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in NOTCH2NLC expanded patients. RESULTS: In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic NOTCH2NLC GGC repeat expansions (≥60 repeats). Intermediate-length GGC repeats (41-59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085, p = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with NOTCH2NLC GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non-Motor Symptoms Scale scores and lower Mini-Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET-plus (11/46) and ET-neuronal intranuclear inclusion disease (10/46) subgroups at 2-8 years of follow-up. CONCLUSION: Our results further supported that NOTCH2NLC GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non-motor symptoms. Further long-term follow-up and subtype studies will help to define the role of NOTCH2NLC in ET.
BACKGROUND AND PURPOSE: NOTCH2NLC GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with NOTCH2NLC repeat expansions versus non-expansions and describe distinctive clinical features of repeat expanded patients with long-term follow-up according to the new tremor classification. METHODS: Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in NOTCH2NLC were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in NOTCH2NLC expanded patients. RESULTS: In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic NOTCH2NLC GGC repeat expansions (≥60 repeats). Intermediate-length GGC repeats (41-59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085, p = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with NOTCH2NLC GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non-Motor Symptoms Scale scores and lower Mini-Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET-plus (11/46) and ET-neuronal intranuclear inclusion disease (10/46) subgroups at 2-8 years of follow-up. CONCLUSION: Our results further supported that NOTCH2NLC GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non-motor symptoms. Further long-term follow-up and subtype studies will help to define the role of NOTCH2NLC in ET.